Guanfacine hydrochloride has a pH dependent solubility, being more soluble at low pH values than higher pH values. The dissolution rate of the substance is directly related to the solubility of this substance in the given medium. In the case of basic drugs such as guanfacine HCl dissolution rate thus is higher at low pH values compared to higher pH values. In case of sustained or extended release formulation this characteristic of the API is not desired due to the fact that drug release rate will be higher at earlier parts of the gastrointestinal tract than later segments of the gastrointestinal tract where the pH is higher. This in vivo situation can clearly be observed with dissolution studies where drug release rate is higher in low pH medium, such as pH 1.2 HCl medium, than pH 6.8 Phosphate buffer.
In such cases sustained release can not be maintained since most of the API will be dissolved in stomach at a higher rate compared to the intestines resulting in peak plasma levels in very early stages of absorption which decreases as the formulation reaches to the intestines.
Different sustained release formulations of guanfacine HCl were previously described in U.S. Pat. Nos. 5,854,290; 6,287,599; 6,811,794 where pH dependent release of guanfacine was modified using a pH dependent polymer and an acid in the sustained release formulations. A pH dependent polymer was used to limit the dissolution from sustained release formulation whereas an acid was used to create a micro pH environment to improve the dissolution of guanfacine HCl in basic media. However, the dissolution in acidic media was still higher than the dissolution of sustained release tablets in basic media.
US 2011/0262496 relates to drug therapy formulations for reducing the side effects associated with a therapeutic. In some embodiments, US 2011/0262496 provides a reduction in sleep- and diet-related side effects associated with a therapeutic. The formulation may be in the form of a nanoparticle having a mean diameter of 100-500 nm. The nanoparticles are obtained by milling for several hours.
US 2003/0152622 is directed to an erodible, gastric-retentive drug dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient, the dosage form comprising the pharmacologically active agent incorporated in a matrix of at least one biocompatible, hydrophilic polymer that (a) swells in the presence of water in gastric fluid such that the size of the dosage form is sufficiently increased to provide gastric retention in the stomach of a patient in whom the fed mode has been induced, (b) gradually erodes within the gastrointestinal tract over a determinable time period, and (c) releases the active agent throughout the determinable time period.